508 Diabetes Volume 69, April 2020 Remnants of the Triglyceride-Rich Lipoproteins, Diabetes, and Cardiovascular Disease Alan Chait,1 Henry N. Ginsberg,2 Tomas Vaisar,1 Jay W. Heinecke,1 Ira J. Goldberg,3 and Karin E. Bornfeldt1,4 Diabetes 2020;69:508–516 | https://doi.org/10.2337/dbi19-0007 Diabetes is now a pandemic disease. Moreover, a large LDL-C levels by increasing LDL receptor activity are widely number of people with prediabetes are at risk for de- used to prevent CVD. However, despite the benefitof veloping frank diabetes worldwide. Both type 1 and type statins and marked reduction of circulating LDL-C levels, 2 diabetes increase the risk of atherosclerotic cardio- patients with diabetes continue to have more CVD events vascular disease (CVD). Even with statin treatment to than patients without diabetes, indicating significant re- lower LDL cholesterol, patients with diabetes have a high sidual CVD risk. A recent new classification system of residual CVD risk. Factors mediating the residual risk are T2DM, based on different patient characteristics and risk of incompletely characterized. An attractive hypothesis is diabetes complications, divides adults into five different that remnant lipoprotein particles (RLPs), derived by clusters of diabetes (3). Such a substratification of T2DM, lipolysis from VLDL and chylomicrons, contribute to this which takes insulin resistance and several other factors into residual risk. RLPs constitute a heterogeneous popula- account, could perhaps help tailor treatment to those who tion of lipoprotein particles, varying markedly in size and would benefit the most. composition. Although a universally accepted definition fi There are likely to be a number of reasons why cho- is lacking, for the purpose of this review we de ne RLPs fi as postlipolytic partially triglyceride-depleted particles lesterol reduction in patients with diabetes is not suf cient derived from chylomicrons and VLDL that are relatively to reduce CVD events to the levels found in patients enriched in cholesteryl esters and apolipoprotein (apo)E. without diabetes. Atherosclerotic lesions in patients with diabetes tend to be more inflammatory, i.e., have greater PERSPECTIVES IN DIABETES RLPs derived from chylomicrons contain apoB48, while those derived from VLDL contain apoB100. Clarity as to numbers of macrophages (4). Moreover, after cholesterol the role of RLPs in CVD risk is hampered by lack of reduction, intravascular ultrasound studies show less re- a widely accepted definition and a paucity of adequate gression of lesions in people with diabetes (5). Residual CVD methods for their accurate and precise quantification. risk appears to be at least partly linked to elevated plasma New specific methods for RLP quantification would triglycerides and abnormal metabolism of triglyceride-rich greatly improve our understanding of their biology and lipoproteins (TRLs) (6,7), which are conventionally consid- role in promoting atherosclerosis in diabetes and other ered to consist of chylomicrons, VLDLs, and their respec- disorders. tive remnant lipoproteins (remnant lipoprotein particles [RLPs]), many of which are present in intermediate-density lipoproteins (IDLs). Diabetes and Residual Cardiovascular Disease Risk Normal fasting levels of plasma triglycerides are defined Both type 1 (T1DM) and type 2 (T2DM) diabetes mellitus by current clinical guidelines as ,1.69 mmol/L (,150 mg/dL). increase the risk of cardiovascular disease (CVD) (1,2). The The definitions of elevated triglyceride levels vary, but causal relationship of LDL cholesterol (LDL-C) with in- fasting triglyceride levels of 1.69–2.25 mmol/L (150– creased CVD risk is well established, and drugs that lower 199 mg/dL) are often considered moderately elevated and 1Department of Medicine, University of Washington Medicine Diabetes Institute, Corresponding author: Karin E. Bornfeldt, [email protected] University of Washington, Seattle, WA Received 28 September 2019 and accepted 16 January 2020 2Division of Preventive Medicine and Nutrition, Department of Medicine, Columbia © 2020 by the American Diabetes Association. Readers may use this article as University, New York, NY long as the work is properly cited, the use is educational and not for profit, and the 3Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, work is not altered. More information is available at https://www.diabetesjournals New York University, New York, NY .org/content/license. 4Department of Pathology, University of Washington Medicine Diabetes Institute, University of Washington, Seattle, WA diabetes.diabetesjournals.org Chait and Associates 509 fasting triglycerides .2.26 or 2.83 mmol/L (200 or 250 genes linked to elevated levels of triglycerides and CVD mg/dL) are considered high and .5.65 mmol/L (500 mg/dL) risk independently of LDL-C include APOA5 and angio- severely elevated (8). Elevated plasma triglycerides can poietin-like protein 4 (ANGPTL4), an activator and an be due to increased triglyceride production, decreased li- inhibitor of LPL, respectively (14). Loss-of-function mu- polysis of triglycerides, and/or reduced clearance of TRLs tations in ANGPTL3, another gene in the angiopoietin- (7). Moderate hypertriglyceridemia is common in subjects like protein family, is associated with reduced CVD risk at increased risk of CVD, such as patients with T2DM. and lower triglyceride levels as well as lower levels of However, hypertriglyceridemia strongly associates with a LDL-C and HDL-C (familial combined hypolipidemia) (4). host of other potential risk factors, including obesity, It is now widely accepted that hypertriglyceridemia is insulin resistance, increased levels of all apolipoprotein a risk factor for CVD, although whether elevated trigly- (apo)B particles, including RLPs and small-dense LDL, and cerides might be only a biomarker or a direct mediator of low levels of HDL cholesterol (HDL-C) (6,9). CVD remains unclear. More than 40 years ago studies of familial forms of In patients with T1DM, fasting triglyceride levels are hypertriglyceridemia linked elevated triglyceride levels to usually normal (,150 mg/dL) unless diabetes control is an increased risk of CVD (10). Abundant epidemiological ev- poor (9). There are uncertainties about the role of TRLs idence associated triglyceride levels with CVD risk (11,12), in CVD risk in these patients and in patients with T2DM although the risk was often attenuated when adjusted for and normal triglyceride levels. However, data from DCCT/ potential confounders, such as HDL-C (13). Furthermore, EDIC (Diabetes Control and Complications Trial/Epidemio- clinical trials of fibrates and n-3 fatty acids (polyunsaturated logy of Diabetes Interventions and Complications) suggest fatty acids, also often referred to as fish oils) have, with the that total serum apoC3 and apoC3 in HDL are important exception of REDUCE-IT (Reduction of Cardiovascular predictive biomarkers for CVD in adults with T1DM (18). Events With Icosapent Ethyl–Intervention Trial) and Moreover, we recently showed that apoC3 is a CVD risk JELIS (Japan EPA Lipid Intervention Study), been mostly factor in a cohort of T1DM subjects with median triglyceride negative for CVD benefit (7). The STRENGTH (Outcomes levels in the normal range (17). Although there was a strong Study to Assess STatin Residual Risk Reduction With positive correlation between triglyceride levels and serum EpaNova in HiGh CV Risk PatienTs With Hypertriglycer- apoC3 in this cohort, apoC3 appeared to be a stronger risk idemia) trial was recently stopped by the data monitoring factor. These observations suggest that apoC3 and trigly- board due to a low likelihood of success, but the results cerides promote atherosclerosis in T1DM subjects—and have yet to be published. These negative results could have perhaps in other subjects with triglycerides generally in the resulted from inclusion of individuals without hypertri- normal range. One possible explanation is that accumula- glyceridemia in most of the fibrate trials, use of inadequate tion of lipolytic products of chylomicrons and VLDL, i.e., doses or form (ester versus free fatty acid) in most of the cholesterol-enriched RLPs, is the reason for elevated CVD n-3 fatty acid trials, or heterogeneity in the atherogenicity risk rather than the more triglyceride-rich precursors of of the triglyceride-carrying lipoproteins, at least in terms RLPs, chylomicrons and VLDL. Moreover, this hypothesis of triglyceride as a marker of CVD risk, in the study implies that partial defects in the TRL lipolysis pathway, cohorts. Therefore, there is a need to better define the e.g., due to heterozygous loss of LPL or polygenic causes of relationship between plasma triglyceride levels, the apoB reduced lipolysis, would be more atherogenic than total loss lipoprotein particles that carry triglycerides and cholesterol of LPL. Thus, very active lipolysis appears to lead to a rapid (chylomicrons, VLDL, IDL, and RLPs), and the relative removal of both chylomicrons and remnants from the blood atherogenicity of those lipoproteins versus LDL. Increased stream. Heterozygous deficiency of LPL leads to greater understanding of these difficult issues will offer critical postprandial lipemia including the accumulation of more insights needed to facilitate our search for additional IDLs (19) and chylomicron remnants (20), whereas total approaches to CVD prevention and treatment options LPL deficiency actually prevents the formation of RLPs (21). for hypertriglyceridemic patients, especially those with It is therefore